Perinatal Origins of Adult Disease" describes various observations of adult consequences due to altered metabolic/hormonal milieu in-utero or postnatally. Examples include 1] infants born to diabetic mothers (IDM), who, independent of their genetic predisposition, develop obesity and glucose intolerance in later life, and 2J intra-uterine growth restricted infants (IUGR) who develop syndrome X consisting of insulin resistance, obesity, and dyslipidemia with hypertension and coronary artery disease during adult life. To decipher the mechanism(s) by which this phenomenon occurs, we first characterized two rat models: 1] the streptozotocin-induced maternal diabetes where the macrosomic, hyperinsulinemic newborn offsprings develop visceral obesity, hyperinsulinemia, and glucose intolerance as adults; and 2] the prenatally starved mother where the IUGR, hypoinsulinemic newborn offsprings also demonstrate visceral obesity, hyperinsulinemia, and glucose intolerance as adults. Next, we focused on the recently cloned "obesity (ob) gene product (leptin) that is predominantly synthesized by adipocytes, and plays a mitogenic role in promoting fetal growth. We noted that fetal hyperinsulinemia as seen in the IDM increases while hypoinsulinemia seen with IUGR decreases fetal leptin concentrations. In addition, circulating leptin concentrations increased in the adult obese and glucose intolerant offspring of a diabetic mother and IUGR offsprings. Recently, we have demonstrated that leptin administration during the postnatal period alters skeletal muscle uncoupling proteins causing a dose-dependent decline in body weight. Postnatal leptin administration also causes an imbalance in the rat hypothalamic orexigenic (neuropeptide Y, NPY) and anorexigenic (a-melanocyte stimulating hormone, a-MSH) neuropeptides, leading to persistent changes in food intake and body weight in the adult female rat progeny. This observation gives rise to the innovative concept of in-utero/postnatal leptin concentrations predetermining the adult phenotype by "the mechanism of hormonal/metabolic imprinting." Our overall hypothesis is that in-utero/postnatal leptin concentrations with or without altered metabolic substrate availability permanently alter the mechanisms regulating food intake and energy expenditure, thereby predetermining the ultimate adult phenotype. To test this hypothesis, we propose the following specific aim: To examine the effect of postnatal intracerebroventricular (ICV) versus systemic (IP) leptin administration on hypothalamic neuropeptides that regulate food intake, and uncoupling proteins (UCP) that mediate energy expenditure, both of which determine the net body weight gain pattern in 1] the normosomic offspring of a normal rat pregnancy, 2] the macrosomic offspring of a streptozotocin-diabetic rat mother, and 3] the IUGR offspring of a prenatally starved rat mother, at d3, d10, d21, d60, and d180 in males and females. The results of our studies will test the above stated hypotheses and determine the contribution of in-utero and postnatal "leptin" in modifying the mechanisms leading to the adult phenotype predetermined by in-utero metabolic perturbations.